Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by loss of memory, cognition, and behavioral stability. AD afflicts 6-10% of the population over age 65 and up to 50% over age 85. It is the leading cause of dementia and the third leading cause of death after cardiovascular disease and cancer. At present, there are no effective treatments for AD and treatment is limited to the use of symptomatic agents such as the cholinesterase inhibitor, donepezil (Aricept®, Pfizer). The total net cost related to AD in the U.S. exceeds $100 billion annually.
AD is characterised pathologically by the presence of specific lesions in the limbic and cortical regions of the brain. These include intracellular neurofibrillary tangles consisting of hyperphosphorylated tau protein and the extracellular deposition of fibrillar aggregates of amyloid-beta peptides in the form of amyloid plaques (senile plaques). The major components of amyloid plaques are amyloid-beta (A-beta, Abeta or Aβ) peptides of various lengths (39-42 amino acids). A variant thereof, which is the Aβ1-42 (Abeta1-42, Aβ42) peptide, is believed to be the major pathogenic species in AD brain and can act as a seed for amyloid plaque formation. Another variant is the Aβ1-40 (Abeta1-40, Aβ40) peptide.
The identification of mutations in the beta-Amyloid Precursor Protein (beta-APP, β-APP or APP), Presenilin-1 (PS-1) and Presenilin-2 (PS-2) genes that increase Aβ production and lead to early-onset familial forms of AD have given strong support to the “amyloid cascade hypothesis” of AD (Hardy, 2006 Curr Alzheimer Res. 3(1):71-73; Tanzi and Bertram, 2005 Cell 120, 545-555) and therapeutic approaches targeting Aβ production.
There is emerging data on the role of Aβ peptides in other diseases including, but not limited to Down's syndrome (DS), mild cognitive impairment (MCI), cerebral amyloid angiopathy (CAA), inclusion body myositis (IBM) and age-related macular degeneration. Hence, Aβ lowering agents could be beneficial for the treatment of diverse pathologies in which Aβ peptides are implicated. Aβ peptides are generated following proteolytic processing of APP. The generation of Aβ peptides is regulated by at least two proteolytic activities referred to as β-site APP cleaving enzyme 1 (BACE-1) and γ-secretase. APP is initially cleaved by BACE-1 at the N-terminus (Met-Asp bond) of the Aβ domain leading to the secretion of soluble APPβ (sAPPβ) and the retention of a 12 kDa membrane-bound carboxy terminal fragment (CTFβ). The latter is subsequently cleaved by γ-secretase to generate Aβ peptides of varying length and an APP intracellular domain (AICD).
BACE-1 is a type I transmembrane aspartic protease that comprises a large extracellular domain containing the catalytic active site, a single transmembrane domain and a short cytoplasmic tail [Hussain et al. 1999 Mol. Cell Neurosci. 14(6):419-427]. The γ-secretase activity resides within a multiprotein complex containing at least four components: a presenilin (PS) heterodimer, nicastrin, anterior pharynx-defective 1 (Aph-1) and presenilin enhancer 2 (Pen-2). The PS heterodimer consists of the amino- and carboxy terminal fragments generated by endoproteolysis of PS and the two aspartates in the catalytic site are at the interface of this heterodimer.
Therapeutic approaches to lower Aβ production include but are not restricted to inhibition or modulation of BACE-1 and γ-secretase activity (Albert, 2009 Prog Med Chem. 48: 133-61; Beher, 2008 Curr Top Med Chem. 8: 34-37; Panza et al. 2011 Curr Med Chem. 18(35): 5430-5447). However, due to the fundamental role γ-secretase plays in the intramembrane proteolysis of other proteins, the clinical development of γ-secretase inhibitors was hindered by mechanism-based toxicities (Schor, 2011 Ann Neurol. 69: 237-239).
There is a strong need for novel compounds which decrease Aβ production thereby opening new avenues for the treatment of AD. It is an object of the present invention to provide such novel compounds.